Nephropathy is a major complication of both type 1 and type 2 diabetes which causes considerable morbidity and mortality. Despite best current treatments, significant numbers of individuals with albuminuria progress to end stage renal disease. Although the mechanisms underlying this progression are not fully understood, renal lipid and lipoprotein accumulation has been shown to accelerate the development of nephropathy. Renal lipid accumulation triggers an influx of inflammatory cells with subsequent development of glomerulosclerosis, the characteristic lesion of diabetic nephropathy. Glomerulosclerosis is characterized by increased deposition of mesangial matrix, including proteoglycans. Of particular interest, the renal content of the small leucine-rich proteoglycan (SLRP) biglycan is increased in diabetes. TGF-2, which is elevated in diabetes, and is known to be a key mediator of diabetic nephropathy development and progression, also increases mesangial matrix deposition, including increased expression of biglycan. Furthermore, we have shown that TGF-2 increases the size and LDL binding affinity of renal proteoglycans. Thus, increased renal proteoglycan (biglycan) synthesis induced by elevated TGF-2 in diabetes may be responsible for mediating the renal accumulation of lipoproteins. The overall goal of this grant is to test the hypothesis that renal lipid accumulation is mediated through interactions of lipoproteins with renal proteoglycans, especially biglycan. This will be tested by comparing diabetic nephropathy in mice expressing proteoglycan-binding defective LDL with littermates expressing wildtype LDL. To determine if biglycan is the key proteoglycan responsible, diabetic nephropathy will be compared between biglycan deficient and wildtype mice. The experiments outlined in this grant will provide direct in vivo experimental data identifying if proteoglycan mediated renal lipid accumulation contributes significantly to the development and progression of diabetic nephropathy, and if the key proteoglycan is biglycan. This grant will also identify if biglycan serves as a natural inhibitor of TGF-2 in vivo. Thus, the significance of this proposal is that it not only identifies a mechanism linking hyperlipidemia and diabetic nephropathy, but also will identify novel targets to prevent or intervene in the development of diabetic nephropathy. PUBLIC HEALTH RELEVANCE: Potential Impact on Veterans Health Care: Veterans have very high prevalence of diabetes, hyperlipidemia and diabetes complications, including nephropathy. This research will either identify or exclude proteoglycans as a cause of renal lipid accumulation contributing to diabetic nephropathy. The grant will prove the concept in an animal model system and the results can be easily translated into clinical research. The ultimate goal is to identify novel targets for therapeutic intervention, to decrease the morbidity and mortality of diabetic nephropathy.